Targeted Cancer Therapies

Introduction to Targeted Therapies

Economic evaluation of targeted cancer interventions is essential due to their high costs, and analyses should consider both the accuracy of targeting tests and alternative targeting methods, as recommended by the American College of Medical Genetics and Genomics 1

Molecular testing should include EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF mutations, KRAS G12C mutations, MET mutations, NTRK rearrangements, and HER2 mutations for all patients with non-squamous NSCLC, as recommended by the National Comprehensive Cancer Network 2
PD-L1 expression testing should also be performed to assess the potential use of immunotherapy if no targetable genetic mutations are detected 2
For metastatic CRC, molecular testing guides therapy, with RAS wild-type tumors treated with anti-EGFR therapy (cetuximab or panitumumab) for left-sided tumors, as recommended by the National Comprehensive Cancer Network 3
For metastatic CRC, BRAF V600E mutations are treated with encorafenib plus cetuximab for previously treated disease, as recommended by the National Comprehensive Cancer Network 3
For metastatic CRC, HER2 amplification is considered for trastuzumab combinations or trastuzumab deruxtecan, as recommended by the European Society for Medical Oncology 4
For metastatic CRC, MSI-H/dMMR tumors are treated with immune checkpoint inhibitors (PD-1 inhibitors), as recommended by the European Society for Medical Oncology 4
The following table summarizes the recommended targeted therapies for NSCLC:

Mutation	Recommended Therapy
EGFR (exon 19 deletion or exon 21 L858R)	Osimertinib (category 1)
EGFR (exon 20 insertion)	Amivantamab-vmjw + carboplatin + pemetrexed (category 1)
ROS1	Entrectinib, crizotinib, or repotrectinib
KRAS G12C	Adagrasib or sotorasib (second-line or later)

For HER2-negative, HR-positive metastatic breast cancer, after endocrine therapy failure, single-agent chemotherapy or endocrine therapy with targeted agents is considered, as recommended by the American Society of Clinical Oncology 5
For triple-negative breast cancer, PD-L1-positive disease is treated with immune checkpoint inhibitor (atezolizumab plus nab-paclitaxel or pembrolizumab plus chemotherapy) as first-line therapy, as recommended by the American Society of Clinical Oncology 5
For male breast cancer, targeted therapy is guided by HR, HER2, PD-L1, PIK3CA, and germline BRCA mutation status using the same indications as for women, as recommended by the American Society of Clinical Oncology 6
For NSCLC with EGFR mutations, osimertinib is the preferred first-line treatment, with longer median progression-free survival (18.9 vs 10.2 months) and median overall survival (38.6 vs 31.8 months) compared to first-generation EGFR TKIs, as recommended by the National Comprehensive Cancer Network 2, 7
For NSCLC with ROS1 rearrangements, entrectinib, crizotinib, or repotrectinib are recommended as first-line treatments, with entrectinib or repotrectinib prioritized for patients with brain metastases, as recommended by the National Comprehensive Cancer Network 2

For BRAF V600E-mutant mCRC, encorafenib plus cetuximab is recommended after disease progression on at least one previous line of therapy, with a high response rate, as recommended by the National Comprehensive Cancer Network 3
For triple-negative breast cancer, sacituzumab govitecan shows high efficacy after at least two prior therapies, with a significant improvement in overall survival, as recommended by the American Society of Clinical Oncology 5
For BRCA-mutated breast cancer, PARP inhibitors demonstrate high response rates in patients with DNA repair defects, with a significant improvement in progression-free survival, as recommended by the American Society of Clinical Oncology 5
Osimertinib has demonstrated superior efficacy compared to first-generation EGFR TKIs, with longer median progression-free survival (18.9 vs 10.2 months) and median overall survival (38.6 vs 31.8 months), as recommended by the National Comprehensive Cancer Network 7

For patients with targetable mutations, targeted therapy should be prioritized over immunotherapy, regardless of PD-L1 expression levels, due to higher response rates and better tolerability, as recommended by the European Society for Medical Oncology 4, 2
For patients with NSCLC and poor performance status (PS 3-4) who have EGFR mutations, EGFR TKIs are recommended, as recommended by the National Comprehensive Cancer Network 8
For elderly patients with EGFR mutations, EGFR TKIs are preferred, as recommended by the National Comprehensive Cancer Network 8
Concurrent or rapid switching from immunotherapy to targeted therapy (particularly osimertinib) should be avoided due to the risk of increased toxicity, as recommended by the National Comprehensive Cancer Network 2
Response to treatment should be evaluated with CT scans (with or without contrast) after 2 cycles of treatment and then every 2-4 cycles, as recommended by the National Comprehensive Cancer Network 2
Upon disease progression, re-biopsy or liquid biopsy should be performed to determine the mechanism of resistance, as recommended by the National Comprehensive Cancer Network 2